The present invention relates to processes for the preparation of cyclopenta[b][1,4]diazepino[6,7,1-hi]indoles and intermediates and derivatives thereof, which are serotonin 5-hydroxytryptamine 2C (5HT2C) receptor agonists useful for the treatment and prevention of disorders such as obsessive-compulsive disorder, depression, anxiety, schizophrenia, migraine, sleep disorders, eating disorders, obesity, epilepsy, and spinal cord injury.
Obesity is a medical disorder characterized by an excess of body fat or adipose tissue. Comorbidities associated with obesity are Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers, some infertility, and early mortality. As the percentage of obese individuals continues to rise both in the U.S. and abroad, obesity is expected to be a major health risk in the 21st Century. The serotonin 5-hydroxytryptamine (5-HT) receptor is a G-protein coupled receptor which is expressed in neurons in many regions of the human central nervous system. [Wilkinson, L. O. and Dourish, C. T. in Serotonin Receptor Subtypes: Basic and Clinical Aspects (ed. Peroutka, S. J. ) 147-210 (Wiley-Liss, New York, 1991).] The 5HT2c receptor (formerly called the 5HT1C receptor) is a prominent subtype of the serotonin receptor found in the central nervous system of both rats and humans. It is expressed widely in both cortical and subcortical regions. [Julius, D. MacDermott, A. B., Axel, R. Jessell, T. M. Science 241:558-564 (1988).] Studies in several animal species and in humans have shown that the non-selective 5HT2C receptor agonist, meta-chlorophenylpiperazine (MCPP) decreases food intake. [Cowen, P. J., Clifford, E. M. , Williams, C., Walsh, A. E. S., Fairburn, C. G. Nature 376: 557 (1995).] Tecott, et al have demonstrated that transgenic mice lacking the 5HT2C receptor eat more and are heavier than Wild Type mice. [Tecott, L. H., Sun, L. M., Akana, S. F., Strack, A. M., Lowenstein, D. H., Dallman, M. F., Jullus, D. Nature 374: 542-546 (1995).] Compounds of this invention are 5HT2C receptor subtype selective agonists which are selective over other monoamine receptors, cause a reduction in food intake and result in a reduction in weight gain. Other therapeutic indications for 5HT2C agonists are obsessive compulsive disorder, depression, panic disorder, schizophrenia, sleep disorders, eating disorders, and epilepsy.
U.S. Pat. No. 3,914,250 (Oct. 21, 1975) describes 1,4-diazepino[6,5,4-jk]carbazoles as anticonvulsant agents. Compounds of this invention are not carbazoles. Compounds of this invention contain a unique ring system not previously described in the literature. This invention relates to cyclopenta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives which bind to and activate 5HT2C receptors in the CNS and are useful for the treatment of CNS disorders which can benefit from modulation of the 5HT2C receptor.
This invention provides a process for the synthesis compounds of formula I: 
wherein
R is hydrogen or alkyl of 1-6 carbon atoms;
R1, R2 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, fluorinated alkyl of from 1 to 6 carbon atoms, xe2x80x94CN, xe2x80x94NHxe2x80x94SO2-alkyl of 1-6 carbon atoms, xe2x80x94SO2xe2x80x94NHxe2x80x94alkyl of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, fluorinated alkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl, preferably phenoyl or thiophenoyl;
R3, R4 are each independently hydrogen, C1-C6 alkyl, cycloalkyl of from 3 to 7 carbon atoms or xe2x80x94CH2-cycloalkyl of from 3 to 7 carbon atoms;
wherein the dashed line indicates an optional double bond;
as well as intermediates and pharmaceutically acceptable salts thereof.
One group of compounds prepared by this invention are those of formula I, above, in which R is hydrogen and R1, R2, R3, and R4 are as defined above. Another process of this invention provides compounds of Formula I wherein R, R1 and R3 are hydrogen and R2 and R4 are as defined above. In another process of this invention, each of R, R1, R2, R3, and R4 are hydrogen. Each of these processes includes a subset wherein the double bond indicated in Formula I by the dashed line is present and another subset wherein a single bond is present.
These compounds are 5HT2C receptor agonists useful for the treatment or prevention of disorders involving the central nervous system such as obsessive-compulsive disorder, depression, anxiety, generalized anxiety disorder, panic disorder, schizophrenia, migraine, sleep disorders, eating disorders, obesity, epilepsy, and spinal cord injury.
The compounds of this invention contain asymmetric carbon atoms and thus give rise to optical isomers and diastereoisomers. While shown without respect to stereochemistry in Formula I, the present invention provides for preparation of such optical isomers and diastereoisomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
In the definitions of R1 and R2 herein, the fluorinated alkyl and fluorinated alkoxy groups indicate the specified alkyl or alkoxy groups having any amount of fluorine substitution including, but not limited to, groups such as xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94C2F5, xe2x80x94OCF3, etc.
The term xe2x80x9calkylxe2x80x9d includes both straight- and branched-chain saturated aliphatic hydrocarbon groups and cycloalkyl groups. Halogen is defined as Cl, Br, F, and l.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. The processes described herein will be understood to optionally include an additional step of preparing a pharmaceutically acceptable salt of a compound of Formula I, as defined herein, utilizing processes and methods known in the art.
The 5HT2C receptor agonists of this invention are useful for the treatment or prevention in mammals, preferably in humans, of disorders involving the central nervous system such as obsessive-compulsive disorder, depression, atypical depression, bipolar disorders, anxiety, generalized anxiety disorder, schizophrenia, psychoses, personality disorders, organic mental disorders, behavioral disorders associated with dementia or age-related conditions, aggressivity, drug and alcohol addiction, social phobias, sexual dysfunction, panic disorder, migraine, sleep disorders, such as sleep apnea, eating disorders, such as hyperphagia, bulimia or anorexia nervosa, obesity, epilepsy, and premenstrual tension.
This invention also includes methods of utilizing the compounds herein in treatments or preventitive regimens for treatment of central nervous system deficiencies associated with trauma, stroke, neurodegenerative diseases or toxic or infective CNS disorders including, but not limited to, encephalitis or menengitis; or cardiovascular disorders, including thrombosis; gastrointestinal disorders such as malfunction of gastrointestinal motility; and diabetes insipidus. These methods include the improvement or inhibition of further degradation of central nervous system activity during or following the malady or trauma in question. Included in these improvements are maintenance or improvement in motor and motility skills, control, coordination and strength.
Preferred compounds prepared using this invention are those in which R is hydrogen. Especially preferred are compounds which are enantiomerically pure stereoisomers of compounds where R is hydrogen and the pyrrole ring is reduced.
This invention provides a process for preparation of compounds of Formula I, 
wherein R, R1, R2, R3, and R4 are as defined above. The process comprises the following steps, wherein the dashed line indicates an optional double bond and each of R, R1, R2, R3, and R4 may be as defined in the groups above:
a) treating a benzodiazepine compound of the formula: 
with an acylating agent, such as a base in the presence of a polar solvent, to give an acylated benzodiazepine of the formula: 
wherein R1 represents alkyl of from 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, or a benzyl or napthyl group;
b) reacting the acylated benzodiazepine of step a) with a nitrosating agent to provide an acylated nitroso benzodiazepine compound of the formula: 
c) reducing the acylated nitroso benzodiazepine compound of step b) to yield an acylated 1-aminobenzodiazepine compound of the formula 
d) allowing the acylated 1-aminobenzodiazepine compound of step c) to react with a cyclopentanone compound of the formula: 
to provide a cyclopentylideneamino benzodiazepine compound of the formula: 
e) reacting the cyclopentylideneamino benzodiazepine compound of step d) to provide an acylated compound of the formula: 
and either
f) deacylating the acylated compound of step e) to provide a compound of the formula: 
such as with a base in the presence of a polar solvent, which may optionally be reduced; or
g) reducing the acylated compound of step e) to provide a compound of the formula: 
and
h) treating the compound of step g) with a deacylating agent to provide a compound of the formula: 
One embodiment of this invention provides a process for the production of compounds of the formula: 
comprising the steps 1 through 6, above, with a further optional step of reducing the compound to produce a compound of the formula: 
wherein R, R1, R2, R3, and R4 are as defined above.
Another aspect of this invention provides a process comprising steps 1 through 5, above, to provide an acylated compound of the formula: 
followed by reduction of this compound to provide a reduced acylated compound of the formula: 
and a deacylation step to provide a compound of the formula: 
Each of processes described herein further optionally comprise the initial step wherein the benzodiazepine compound of step 1, above, is initially prepared by reduction of a corresponding substituted or unsubstituted benzodiazepinedione, as shown below. 
Each of the processes herein also further comprises the optional step of alkylating the compounds of the formula: 
wherein R1, R2, R3, and R4 are as defined herein, to provide an alkylated compound of the formula: 
wherein R represents an alkyl group of from 1 to 6 carbon atoms.
The following non-limiting scheme further illustrates the synthesis of compounds according to this invention, which may be accomplished from commercially available starting materials or starting materials which can be prepared using literature procedures. 
In Scheme 1, a substituted or unsubstituted benzodiazepinedione is reduced with a reducing agent, such as lithium aluminum hydride or a borane-tetrahydrofuran complex, to give a substituted or unsubstituted benzodiazepine. The basic nitrogen of the benzodiazepine is protected, such as by being treated with an acylating reagent, such as acetic anhydride, in the presence of a base, such as triethylamine or potassium carbonate, in an organic solvent, such as ether or acetonitrile, to give intermediate I. Intermediate I is allowed to react with an organic or inorganic nitrosating agent, such as t-butyl nitrite or sodium nitrite, in the presence of an acid, such as acetic acid or hydrochloric acid, to give nitroso compounds II. The nitroso compounds II are reduced to hydrazines III using a reducing agent, such as zinc powder in acetic acid and water. The hydrazines III are allowed to react with substituted or unsubstituted cyclopentanones in an acid, such as acetic acid, at 25-110xc2x0 C., to give substituted or unsubstituted hydrazones IV. The hydrazones IV are treated with an acid, such as sulfuric acid or p-toluenesulfonic acid, in the presence of water or an alcohol, such as 1-propanol, at elevated temperatures such as 50-110xc2x0 C. to give protected fused indoles V. The protected fused indoles V can be treated with a base, such as NaOH, in a polar solvent, such as water or an alcohol, at elevated temperatures, such as 50-110xc2x0 C. to give the deprotected fused indoles VI, which are products of this invention. Indoles VI can be reduced using catalytic hydrogenation over a catalyst, such as palladium on charcoal, in the presence of a acid, such as trifluoroacetic acid or hydrochloric acid, to give indolines VII, which are products of this invention. In addition, protected fused indoles V can be reduced, such as by catalytic hydrogenation over a catalyst, such as palladium on charcoal, in an organic solvent, such as ethanol, in the presence of an acid, such as trifluoroacetic acid or hydrochloric acid, to give protected fused indolines VIII. Protected fused indolines VIII are racemic or diastereomeric mixtures which can be separated using chiral HPLC to give separated enantiomers or diastereoisomers which can then be treated with an inorganic base, such as NaOH in a polar solvent, such as water or methanol at elevated temperatures, such as 50-100xc2x0 C., to remove the acyl group giving enantiomers or diastereoisomers IX and X which are products of this invention. Fused indolines VIII can also be deprotected using an inorganic base, such as KOH, in a polar solvent, such as a mixture of water and methanol, to give fused indolines VII. Enantiomers of fused indolines VII can also be resolved using a resolving agent, such as benzoyltartaric acid, in an organic solvent, such as an alcohol, to give products of this invention. Treatment of the secondary amine of IX and X with an alkylating agent, such as an alkyl halide, gives XI and XII which are compounds of this invention.
An alternate syntheic route to hydrazines III is described in Scheme 2. Substituted or unsubstituted benzodiazepines I are allowed to react with allyl N-[(mesitylsulfonyl)oxy]carbamate in toluene under reflux to give compounds XII. Compounds XII are allowed to react with a catalytic amount of tetrakis triphenylphosphinepalladium and a base, such as diethylamine, in an organic solvent, such as methylene chloride, to give hydrazines III. Hydrazines III are converted to fused indoles V as described in Scheme 1. 
An alternate route to hydrazones IV is described in Scheme 3. Substituted or unsubstituted benzodiazepines I are allowed to react with an inorganic cyanate, such as sodium cyanate, in an organic solvent, such as acetonitrile, in the presence of an acid, such as trifluoroacetic acid, at elevated temperatures, such as 35-75xc2x0 C. to give ureas XIII. Ureas XIII are treated with an inorganic hypochlorite, such as sodium hypochlorite, in an alcohol-water solution at 0-25xc2x0 C. to give hydrazines III. Hydrazines III in solution are cooled to  less than 25xc2x0 C. and treated with acetic acid and substituted or unsubstituted cyclopentanones and warmed to room temperature to give hydrazones IV. Hydrazones IV are converted to fused indoles V as described in Scheme 1.
It will be understood that the processes of this invention can further include analogous steps wherein the protecting group applied to the optionally substituted benzodiazepines of Formula I in Scheme 1 are other than the acetyl group used above. Other conventional protecting groups known in the art may also be used including, but not limited to alkyl and acyl chlorides, alkyl or aryl chloroformates, such as ethylchloroformate and benzyl chloroformate and dialkylcarbonates, and para-nitro benzene sulfonyl chloride.
The acylation steps of this invention are understood to include reactions of the appropriate compound with any acylating agent and reaction conditions known in the art. Useful in these steps are acylating agents include acid halides and esters or anhyrides of the appropriate aliphatic carboxylic acid. Useful acid halides include acetyl chloride, propionyl chloride, isobutyryl chloride, benzoyl chloride, etc. Acid anhydrides include acetic anhydride and benzoic anhydride. Similarly, alkylation steps herein are understood to include any relevant alkylating agents and conditions known in the art. These include, but are not limited to the use of alkyl halides, such as methyl iodide, or alkyl tosylates or aldehyde alkylating agents in the presence of an applicable reducing agent.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known pharmaceutically acceptable acids. The processes herein will be understood to include an optional additional step of forming a salt form of the products via standard addition reactions with any pharmaceutically acceptable organic or inorganic acid.
A method of resolving the (R,R) enantiomer from racemic mixtures of these compounds comprises the steps of:
a) dissolving about 1 equivalent of the racemic compound mixture of a product of this invention in a solubilizing amount of an alcohol resolving agent at a temperature of from about 50xc2x0 C. to the reflux temperature for the alcohol, preferably between about 50xc2x0 C. and 70xc2x0 C., under an inert atmosphere, to create a resolving solution;
b) treating the resolving solution of step a) with from about 0.1 to about 0.35 equivalents of dibenzoyl-L-tartaric acid, preferably from about 0.15 equivalents to about 0.3 equivalents, more preferably from about 0.23 to about 0.27 equivalents, most preferably about 0.25 equivalents to precipitate the desired (R,R) enantiomer from the resolving solution as the corresponding tartaric acid salt form; and
c) separating the desired enantiomer from the resolving solution through conventional means, such as filtration.
It will be understood that this process may be followed by additional steps of filtration and purification to enhance the purity and yield of the desired enantiomer product in question.
In step b) it is preferred that the temperature of the resolving solution be maintained at a temperature at or above about 50xc2x0 C., preferably nearer to the reflux temperature of the alcohol in question. The alcohol component of step a) may be comprise a single alcohol or a combination of two or more alcohols selected from those known in the art into which the compound in question can be dissolved. Among the preferred alcohols are the commercially available and relatively low boiling alcohols comprising 10 carbon atoms or less including methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, cyclohexanol, etc.
It will also be understood that the (S,S) enantiomer of the racemic mixture mentioned above could then be purified and collected from the remaining resolving solution described above after collection of the (R,R) tartaric acid salt.
An analogous method for resolving the (S,S) enantiomer from the racemic mixtures of compounds of this invention, the method comprising the steps a) through c) listed above, with dibenzoyl-D-tartaric acid being used in place of dibenzoyl-L-tartaric acid in step b). Comparably, the (R,R) enantiomer can be collected and purified by conventional means from the remaining solution after the tartaric acid salt form of the (S,S) enantiomer is precipitated and removed in this analogous method.